Alzheimer's disease (AD) is the most common neurodegenerative disorder, affecting 10% of people over the age of 65 and 50% of the population over the age of 85. Extraneuronal plaques consisting of ?-amyloid (A?) peptides and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated twisted filaments of the microtubule-associated tau protein are two major pathological hallmarks of AD. Multiple lines of evidence suggest that overproduction/aggregation of A? in the brain is the prime culprit for AD pathogenesis, while hyperphosphorylated tau has been found in multiple neurodegenerative diseases. Therefore, identification of factors involved in modulation of A? generation and tau hyperphosphorylation may be crucial for disease intervention. Using the Random Homozygous Gene Perturbation (RHGP) technology, we have identified a novel gene, fg01, and found that overexpression of the FG01 protein can inhibit both A? generation and tau phosphorylation. Furthermore, we have demonstrated the underlying mechanism: i.e., FG01 can interact with adenylate cyclases to facilitate cAMP synthesis, upregulating PKA activity to phosphorylate and inactivate GSK-3, which in turn affects A? generation and tau phosphorylation. We are now generating transgenic mice that specifically overexpress FG01 in the brain. To further investigate the functions of FG01 in vivo, we propose the following aims: (1) to characterize brain-specific FG01 transgenic mice;and (2) to cross FG01 transgenic mice with 3XTg-AD mice and examine the effects of FG01 on reducing A? generation, tau phosphorylation and the activities of PKA and GSK-3 in vivo, as well as on alleviating other AD- like phenotypes/abnormalities. This work will provide major insight into the involvement of the novel gene FG01 in the temporal and spatial progression of AD pathogenic events and may potentially elucidate new therapeutic targets. PUBLIC HEALTH RELEVANCE: The two major hallmarks of AD pathologies are extracellular amyloid plaques and intraneuronal neurofibrillary tangles (NFTs), whose major components are A? and hyperphosphorylated tau, respectively. Identification and characterization of genes involved in A? generation and tau phosphorylation are critical for understanding AD pathogenesis. We have recently identified a novel gene, fg01, whose overexpression has been found to reduce A2 production, tau phosphorylation, and GSK-3 activity through modulating adenylate cyclase and PKA activity in vitro. In addition to being important to AD pathogenesis, both PKA and GSK-3 are critical for multiple patho/physiological processes such as memory/cognition, diabetes and tumorigenesis. Therefore, developing transgenic mice that overexpress FG01 in the brain and studying the physiological functions of FG01 in vivo will provide important insights into AD pathological processes. Moreover, the FG01 transgenic mouse model will have potential in developing novel diagnostic and therapeutic methods for multiple diseases including AD, diabetes and cancers.